Kendra Sweet, MD, sheds light on data regarding treatment discontinuation and how they impact patients with chronic myeloid leukemia.
Kendra Sweet, MD
Discontinuation of treatment with a tyrosine kinase inhibitor (TKI) is feasible for a subset of patients with chronic myeloid leukemia (CML), explained Kendra Sweet, MD.
Recent findings from clinical trials have paved the way to determine effective criteria for patients to meet to make them eligible for this option. For example, long-term follow-up data from the Stop Imatinib (STIM1) study indicate that imatinib (Gleevec) can be safely discontinued in patients who have had a sustained deep molecular response and no late molecular recurrence.
Imatinib was prospectively discontinued in 100 patients with CML who had undetectable minimal residual disease (MRD) for at least 2 years. At a median molecular follow-up after treatment discontinuation of 77 months, molecular recurrence-free survival was 43% at 6 months and 38% at 60 months. Sixty-one patients lost undetectable MRD at a median of 2.5 months. None of the patients experienced disease progression.
Additional studies with similar and impactful outcomes include the EURO-SKI and ENESTop trials, Sweet added. In December 2017, the FDA updated the label for nilotinib (Tasigna) with a provision stipulating that patients with Philadelphia chromosome-positive CML in the chronic phase who have received the BCR-ABL TKI for at least 3 years and have achieved specific predetermined criteria may be eligible to stop treatment, based on data from ENESTop and ENESTfreedom. To discontinue therapy, patients must achieve a sustained deep molecular response of MR4.5 (BCR-ABL1 International Scale ≤ 0.0032%).
In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Sweet, an assistant member in the Department of Malignant Hematology of Moffitt Cancer Center, shed light on these data regarding treatment discontinuation and how they impact patients with CML.Sweet: There are a number of clinical trials that have been looking at the possibility of discontinuing this class of drugs in a select subset of patients with deep molecular responses who have maintained those responses for a certain period of time. Basically, in every study that’s been done here, the results are strikingly similar. We have consistently seen about 50% of patients relapse, particularly early on. The others are able to maintain what we call a prolonged treatment-free remission. Therefore, in my presentation, I reviewed these different trials that have been completed and published.The first discontinuation trial was the STIM1 trial, which was a study done in France starting in 2007. They enrolled 100 patients who were all being treated with imatinib. These patients maintained those deep responses we mentioned earlier for a minimum of 2 years. They then discontinued imatinib and were followed off treatment until molecular relapse. The data from that study are the oldest data we have now. The long-term follow-up was published about 1.5 years ago. There was a 77-month median follow-up time, and 38% of patients remained off treatment. That was the first sort of proof-of-principle study showing that discontinuing therapy for a subset of patients is feasible.
The largest trial in this space done to date is called EURO-SKI. It enrolled 848 patients in Europe on all available TKIs, and 448 of them were on imatinib. Again, we saw very similar data. We saw slightly higher rates of treatment-free remission on that study. This was likely because of less stringent criteria for restarting therapy. That study, again, was able to help define criteria for patients to be eligible to stop therapy.
The final study I spoke about was the ENESTop trial. It was a trial looking at patients treated with nilotinib as second-line therapy; they were treated with imatinib for frontline therapy. Patients remained on nilotinib for a certain period of time and then came off treatment. The data is now out to 144 weeks, and most patients who relapsed did so early on. Therefore, even in second-line therapy, if you’re choosing patients appropriately, it’s OK to take them off treatment.There are definitely pretty well-defined criteria at this point. In 2016, the National Comprehensive Cancer Network actually established its own criteria that will be what most people in the United States follow. There are quite a few criteria, but if patients meet all of them then they are eligible to discontinue. Minimum time on treatment is 3 years, and minimum time of deep molecular response is 2 years. People who are able to be closely monitored, who never had highrisk disease, who never had any signs of resistance—these are the patients who are best suited for this.You get both ends of the spectrum; you definitely see every kind of response across the board. Some people, from the minute they are diagnosed with CML, want to come off treatment. That is probably more of the newer diagnoses. The patients who have been treated for many years, in my opinion, are the ones who are a little more hesitant to discontinue. It was sort of drilled into them that this was lifelong treatment and they can never come off. It’s a little harder to communicate this to some patients. Some data suggest that these are the patients who will even do better, the ones who have been on treatment the longest.
Some people are afraid of relapsing and progressing, although that hasn’t happened in any of these studies. It’s not an unrealistic daraconcern, though. Some patients are scared they won’t regain their prior response if they have to restart treatment. It’s almost an idea of, “Why mess with success?”Absolutely. There is a lot being done right now to understand which patients relapse and which don’t. What’s the fundamental difference between these 2 groups? It’s still unclear. A lot of people would assume that there is some sort of immune surveillance that allows a patient to stay in remission. For some people, the leukemia is escaping the immune system. There are upcoming clinical trials with second drugs looking at patients who have stopped treatment, relapsed, then restarted treatment on a TKI. We might be adding a second drug.Not at the moment. We are definitely further away from success in myeloid malignancies when it comes to CAR T cells than any lymphoid malignancy. Finding an appropriate target has been a huge challenge. Additionally, we have very successful therapy for patients with CML. Our life expectancy is the same as the general population. It’s hard, in some cases, to think about exposing someone to that kind of toxicity.
Etienne G, Guilhot J, Rea D, et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35(3):298- 305. doi: 10.1200/JCO.2016.68.2914.